Wallace L. McKeehan

Professor, Texas A&M Regents and Distinguished Professor Emeritus

Education and Training

Dr. McKeehan has been Professor at the Institute of Biosciences and Technology (IBT) at the Texas A&M Health Science Center Houston Campus since 1993. He held the J.S. Dunn Endowed Professorship 1993-2014. He has a joint appointment in the Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center and the Department of Biochemistry and Biophysics at Texas A&M University. He is an associate member of the Intercollegiate Faculty of Nutrition (IFN) and Interdisciplinary Faculty of Reproductive Biology (IFRB) within Texas A&M, member of the Cardiovascular Institute (CVRI), College of Medicine, Texas A&M Health Science Center, member of the Graduate Faculty of Biomedical Sciences at the University of Texas-Houston, and Adjunct Professor in Molecular and Cellular Biology at Baylor College of Medicine. He founded and served as Director of the Center for Cancer Biology and Nutrition and later the Center for Cancer and Stem Cell Biology until 2012.

Research Interests

Failure to communicate underlies cancer and other diseases. Tissues are comprised of a society of diverse cell types that similar to human societies must communicate properly to maintain normal function, peace, tranquility and good health. The failure to communicate properly underlies most tissue dysfunctions and disease. The laboratory studies how the chemical signals (polypeptide growth factors and cytokines) in the local tissue environment control growth and specialization of different cell types of the prostate, the liver, the vascular system and neural tissue. These signals determine the normal development and function of the tissues while aberrations result in tissue dysfunction and diseases, such as cancer, stroke, atherosclerosis, liver, and neural disease. These signaling systems which are comprised of a signal polypeptide from one cell type and a reception system on another are the basis for communication among cells in tissues, but also serve as sensors of signals like hormones and nutrients that come from outside the tissues. The cellular reception system for many signal polypeptides consists of a transmembrane protein whose external domain interacts with signal polypeptides and an intracellular domain which is a protein kinase enzyme which activates metabolic pathways that control cell growth, function, and gene expression.

The Fibroblast Growth Factor (FGF) signaling system is a ubiquitous regulatory system that controls cell to cell communication during embryogenesis and cellular homeostasis within adult tissues. The FGF family is unique in the way that it is intimately interwoven with the peri-cellular matrix through heparan sulfate proteoglycans which are an integral part of the signaling system. The system senses changes in the local environment and transmits them to the interior of cells for a response. The laboratory seeks to understand the molecular mechanisms of assembly of components of the FGF signaling system, its role in homeostasis of prostate, liver and the cardiovascular systems and their dysfunction that results in disease. Technologies employed in the laboratory include recombinant DNA technologies, protein chemistry, expression of recombinant proteins in bacteria, yeast, insect cells and mammalian cells, primary cell culture and tissue reconstitutions, monoclonal antibodies and hybridomas, mouse transgenics and proteomics and nanotechnology.

Mouse models of human diseases--prostate cancer, hepatoma and liver diseases. A major effort has been in exploitation of mouse genetic technologies to build new mouse models of human prostate and liver diseases by manipulation of both signals and reception in the different cell populations that comprise different compartments in adult parenchymal organs. Only recently has the importance of the communication among diverse cell populations in the microenvironment to health and disease in addition to the primary functional parenchymal cell. Two-way FGF signaling between the stromal and epithelial compartments as well as vascular and immune system cells maintains normal health and function of the organ. Breakdown in communication disrupts the balance and results in autonomy of epithelial cells observed in cancer. The laboratory was the first to show in the early 90's using prostate cancer as a model that FGF signaling was receptor isotype-specific depending on cell context and cell-specific co-factors.

FGF signaling in cholesterol homeostasis, metabolic syndrome and liver diseases. In addition to the ubiquitous role of the FGF signaling family in cellular homeostasis, mouse models and human mutations have revealed unsuspected roles of FGF signaling in endocrine metabolic control. These include cholesterol to bile acid, lipid, glucose and calcium phosphate metabolism and associated pathologies. The family has been implicated in the starvation response, obesity, diabetes and diseases associated with metabolic syndrome. This includes non-alcoholic fatty liver disease. These activities work in partnership with co-factors called klothos in addition to heparan sulfate. Surprisingly, in contrast to the cellular activities of FGF signaling that are involved in tumor promotion, the metabolic roles of FGF signaling are not directly mitogenic and coincident with a role in tumor suppression. The laboratory was first to implicate FGF signaling in control of metabolic homeostasis in 2000 opening up the subfield of endocrine activities of circulating endocrine FGFs as opposed to their canonical roles in local cell to cell communication.

Preventing cancer at its mitotic origin through mitotic cell death. Although resident FGF signaling systems in epithelial cells mediates homeostasis-promoting communication with the tissue environment, acquisition of an ectopic member of the family in epithelial cells can be a strong promoter of progression to malignancy. However, the promotion role of FGF signaling alone is insufficient to support full malignancy. It works in cooperation with loss of tumor suppressors that function to kill cells that acquire genetic defects that contribute to the genetic plasticity that is a common property of all cancers.

The analysis of cancer genomes is revealing what was suspected over 100 years of observation and treatment. All cancers are different and capable of evading and surviving a wide variety of therapies. A therapy designed for one type of cancer often does not work for another. Diverse cancers exhibit hundreds of genomic differences that cannot be predicted from the normal genome of the patient or from the genome of a precursor to the current cancer. The only common property of all cancers is aneuploidy, too few or too many chromosomes. Aneuploidy happens as a consequence of survival of a random low frequency error in life's most fundamental and essential process, cell division. Frequency can be influenced by environmental factors. Based on the discovery in 1993 of the novel protein, LRPPRC, our research group described a novel network of dual function microtubule- and mitochondrial-associated proteins that sense an error during cell division that could cause aneuploidy. When an aneuploid division threatens, lethal mitochondria that are normally cleared by a process known as mitophagy unite to kill the defective cells through a process called mitotic cell death even before they can complete the defective cell division and over time give rise to cancer. Enhancement of this mechanism may be a way to prevent initiation of cancers in general at their source and eventually the most effective point of prevention and treatment of cancers in general.